SAFETY OF CREATINE SUPPLEMENTATION
ADAM M. PERSKY
1AND ERIC S. RAWSON
21
Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA
2
Department of Exercise Science and Athletics, Bloomsburg University, Bloomsburg, PA 17815, USA
Abstract:
The literature on creatine supplementation supporting its efficacy has grown rapidly and has included studies in both healthy volunteers and patient populations. However, the first rule in the development of therapeutic agents is safety. Creatine is well-tolerated in most individuals in short-term studies. However, isolated reports suggest creatine may be associated with various side effects affecting several organ systems including skeletal muscle, the kidney and the gastrointestinal tract. The majority of clinical studies fail to find an increased incidence of side effects with creatine supplementation. To date, studies have not found clinically significant deviations from normal values in renal, hepatic, cardiac or muscle function. Few data are available on the long-term consequences of creatine supplementation
1. INTRODUCTION
Creatine is an endogenous molecule whose primary role is to act as an ‘energy buffer’. Supraphysiologic doses of creatine have been shown to increase muscle stores of creatine and phosphocreatine, enhance muscle strength, reduce fatigue during exercise and improve exercise performance [see Branch (2003) for a meta- analysis]. Furthermore, there is a growing body of literature on pre-clinical and clinical evidence that creatine has a positive therapeutic outcome in various neuro- logical or muscular diseases.
While creatine is well tolerated by most individuals in short-term studies, anecdotal reports and a small number of case-reports suggest that creatine may be associated with various side effects ranging from muscle cramping and gastroin- testinal discomfort to renal dysfunction. Safety, whether it is a drug, food or supplement, does not imply the product is harmless, but that the therapeutic (or nutritional) benefits outweigh the risks of side effects for the intended population.
As an example, the cholesterol-lowering agent Baycol (cerivastatin) was as effective 275
G.S. Salomons and M. Wyss (eds.), Creatine and Creatine Kinase in Health and Disease, 275–289.
© 2007 Springer.
276 Persky and Rawson
as other statin medications in lowering cholesterol; however, cerivastatin caused severe muscle damage prompting its removal from the market in August 2001 (Charatan, 2001). Adverse events such as severe muscle damage are unacceptable for drug classes for non-life threatening diseases. This risk to benefit ratio helps classify compounds into categories of high therapeutic index (e.g., most over- the-counter medications) or low therapeutic index (e.g., medications that are routinely monitored such as warfarin or lithium). Creatine would be clinically useful if the desired therapeutic effects (e.g., increased muscle strength, reduced fatigue) outweighed the undesired pharmacologic/toxicologic effects (e.g., muscle cramping).
The purpose of this chapter is to summarize the evidence related to the safety of creatine supplements. Although there are safety data available from studies of creatine supplementation in animals, experimental data from animal models may not be directly applicable to the effects of creatine in humans. For instance, Green et al. (1996b) reported no increase in muscle creatine content in rats ingesting creatine in amounts equivalent to the dosages used in human studies. Additionally, creatine uptake is significantly enhanced in the presence of insulin in human skeletal muscle (Green et al., 1996a,b; Preen et al., 2003; Robinson et al., 2000), but to a much lesser extent in rat skeletal muscle (Koszalka et al., 1972). Most recently, species differences (rats vs. mice) in the response to creatine supplementation have been reported (Kreider, 2003; Tarnopolsky et al., 2003). With that in mind, this chapter focuses on data regarding the safety of creatine supplementation from clinical trials and case studies.
2. SAFETY FINDINGS 2.1. Muscle Dysfunction
Creatine supplementation has been associated with increased muscle dysfunction
(i.e. cramps, muscle strains, etc.) in the popular media. Increased muscle creatine
content subsequent to creatine supplementation is associated with increased total
body water (Powers et al., 2003) and increased compartment pressure (Hile
et al., 2006). This resulted in the speculation that creatine supplementation could
cause muscle dysfunction. In theory, increased muscle phosphocreatine levels
resulting from creatine supplementation may reduce muscle dysfunction, as it is
known that exogenous phosphocreatine reduces muscle damage in cardiac tissue
as evidenced by decreased efflux of cardiac muscle proteins into the blood (Saks
et al., 1996; Saks and Strumia, 1993). In fact, phosphocreatine is used as a cardio-
protective agent during heart surgery and to reduce infarct size after myocardial
infarction (Saks et al., 1996; Saks and Strumia, 1993). The effects of creatine
supplementation on mild and severe indices of skeletal muscle dysfunction have
been studied in cross-sectional studies, clinical trials, and case studies, as outlined
below.
2.1.1. Cramping
Muscle cramping in creatine users has been reported by some groups. However, placebo or non-creatine user groups were not included for comparison, so that the relationship between creatine and muscle cramps cannot be determined from these studies (Greenwood et al., 2000; Juhn et al., 1999). A series of open label studies by Greenwood et al. (2003b,c) and one retrospective study (Schilling et al., 2001) reported either similar instances of muscle dysfunction (i.e. cramping, muscle tightness, strains, injuries, etc.) between creatine and non-creatine users or fewer instances of muscle dysfunction in creatine users (Greenwood et al., 2003a).
Recently, Watson et al. (2006) reported no increase in cramping in creatine- supplemented subjects following dehydration and an 80 minute exercise heat tolerance test (33.5
C, 41% relative humidity). In this study, plasma sodium and potassium, and the dehydration levels following exercise, were unaffected by creatine ingestion, so it is not surprising that there was no increase in cramping (Watson et al., 2006). Currently, there appears to be no empirical evidence linking creatine to muscle cramps.
2.1.2. Muscle damage
Reportedly, creatine ingestion has no effect on indices of muscle damage (e.g.
blood creatine kinase or lactate dehydrogenase under resting conditions) (Kreider et al., 2003; Mihic et al., 2000; Robinson et al., 2000; Schilling et al., 2001).
Three clinical studies have examined the interaction between creatine supplemen-
tation, extreme exercise, and muscle damage (Rawson et al., 2001, 2007; Santos
et al., 2004). Rawson et al. (2001, 2007) found no effect of creatine on markers of
muscle damage (decreased strength, decreased range of motion, increased muscle
soreness, and increased serum creatine kinase and lactate dehydrogenase activity)
following 50 high-force eccentric contractions of the elbow flexors or a high-
repetition squat exercise challenge. These data were supported in a study by
Warren et al. (2000) using an animal model. Santos et al., (2004) reported that
creatine supplementation attenuated the increase in plasma creatine kinase (by
19%), prostaglandin E
2(by 61%), and tumor necrosis factor- (by 34%) and
eliminated the increase in plasma lactate dehydrogenase following a 30 km run,
indicating less muscle damage. Collectively, clinical studies of the interactions
between creatine supplementation and extreme exercise stress indicate that creatine
supplementation does not exacerbate muscle damage (Rawson et al., 2001, 2007)
and might protect muscle from damage during certain types of stressful exercise
(Santos et al., 2004). It is important to note that serious adverse events associated
with severe muscle damage (i.e. rhabdomyolysis), which may occur infrequently
(1 in 10,000 exposures), are difficult to detect in the small clinical trials typically
conducted on creatine supplementation (n < 50). The effects of creatine supplemen-
tation on indirect markers of muscle damage from double-blind placebo-controlled
trials are described in Table 1.
278 Persky and Rawson
Table 1. Effects of creatine supplementation on indices of muscle damage in double-blind placebo- controlled trials .
Outcome Variable Exercise Challenge Reference
Ø in resting plasma CK - Mihic
et al., 2000
Ø in resting serum CK - Robinson
et al., 2000 Ø in post-exercise serum CK and LDH,
ROM, strength, DOMS
50 maximal eccentric contractions of the elbow flexors
Rawson et al., 2001 Ø in post-exercise serum CK and LDH,
ROM, strength, DOMS
5 sets of 15-20 squats with 50% of 1-RM
Rawson et al., 2007
↓ in post-exercise plasma CK (19%), PGE
2(61%), TNF- (34%) and LDH (100%)
30 km run Santos
et al., 2004
Note: Ø indicates no effect of creatine; ↓ indicates a decrease following creatine ingestion; ↑ indicates an increase following creatine ingestion. CK = creatine kinase, LDH = lactate dehydrogenase, ROM = range of motion, DOMS = delayed onset muscle soreness, PGE
2= prostaglandin E
2, TNF- = tumor necrosis factor .
2.1.3. Rhabdomyolysis
Despite the intense media scrutiny on creatine supplementation, few cases of severe rhabdomyolysis in creatine users have been reported in the literature (Kuklo et al., 2000; Robinson, 2000; Sandhu et al., 2002; Sheth et al., 2006).
Robinson (2000) reported compartment syndrome and severe rhabdomyolysis in a patient who had been taking five times the recommended dosage of creatine (25 g/day) for one year and had performed three hours of lower extremity exercise the day before. Thus, it is unclear if the rhabdomyolysis was precipitated by the high- dose creatine supplementation, was a result of stressful unaccustomed resistance exercise, or a combination of the two. Similarly, rhabdomyolysis and compartment syndrome have been reported following stressful exercise in patients who had been ingesting creatine in combination with other supplements (e.g. ephedrine, natural diuretics) (Kuklo et al., 2000; Sandhu et al., 2002). Sheth et al. (2006) described a case of rhabdomyolysis in a creatine user in the days following arthroscopic knee surgery. It is uncommon, but post-operative rhabdomyolysis has been reported.
Overall, it is unclear what role creatine supplementation played in these cases of severe rhabdomyolysis. It may be that in those who are predisposed to exercise- induced rhabdomyolysis, the combination of creatine supplementation and stressful unaccustomed exercise worsens symptoms compared to exercise alone, although this is speculative.
2.2. Dehydration
Creatine is often incorrectly associated with dehydration. In fact, creatine supple-
mentation increases total body water (Powers et al., 2003) and is more correctly
referred to as a hyper-hydrating agent. Powers et al. (2003) used deuterium oxide and sodium bromide dilution analyses to demonstrate a 1.4 liter and 2.0 liter increase in total body water following 7 and 21 days of creatine supplementation, respectively.
It has been proposed that creatine supplementation may bind water inside the muscle cell, making it unavailable for heat loss through the evaporation of sweat. However, Powers et al. (2003) reported that fluid distribution was unaffected by creatine supplementation (i.e. the intra- and extracellular water ratios were unaltered).
Several researchers have investigated thermoregulatory responses and exercise performance (Kern et al., 2001; Kilduff et al., 2004; Mendel et al., 2005; Vogel et al., 2000; Volek et al., 2001; Watson et al., 2006) in creatine-supplemented individuals following heat stress and/or hypohydration (Table 2). Collectively, these studies demonstrate that creatine-induced hyper-hydration does not impair thermoregulatory or metabolic responses to prolonged exercise in the heat. In fact, creatine may attenuate thermoregulatory responses and prevent heat related injuries and performance decrements (Kilduff et al., 2004). For instance, Kilduff et al. (2004) reported decreased heart rate, perceived leg fatigue, rectal and body temperature, and sweat rate in creatine-supplemented individuals cycling to exhaustion in the heat (see Table 2). In the most comprehensive study to date, Watson et al. (2006) demon- strated that creatine supplementation does not adversely affect a number of variables spanning thermoregulatory, metabolic, and perceived responses to exercise in the heat in hypohydrated individuals (see Table 2). Although it has been theorized that increased total body water associated with creatine ingestion may cause thermoreg- ulatory disturbances when exercise is combined with heat stress, the data do not support this.
2.3. Renal Dysfunction
Although the kidney has many physiologic functions it is most noted for its
excretory function. The kidneys are responsible for predominantly removing small,
hydrophilic molecules from the blood. Creatine and its major metabolite, creatinine,
are both cleared from the blood by the kidney. Creatinine is an important clinical
marker for renal function; more specifically, creatinine clearance is an indicator of
glomerular filtration rate (GFR). Creatinine clearance is most frequently calculated
from a single serum creatinine sample and the subsequent use of the Cockcroft-
Gault equation, although other equations are available. The use of serum creatinine
as a marker for renal function requires several assumptions, including: 1) the
daily anabolic production of creatine is constant and 2) the conversion of creatine
to creatinine is constant, and non-constant sources do not exist. During creatine
supplementation, the first assumption is violated because supraphysiologic doses
consumed far exceed daily endogenous production (daily liver production ∼1 g/d,
typical dosing 3–20 g/day). This in turn reduces endogenous creatine synthesis
(Walker and Hannan, 1976). The second assumption of constant conversion is not
violated however, as creatine stores increase with creatine dosing, so does serum
creatinine. This is expected assuming the rate of degradation into creatinine is
Table2
. Effects of creatine supplementation on thermoregulatory responses and exercise performance in heat-stressed and hypohydrated individuals . Effect of Creatine on Outcome Variables Exercise/Environmental stress Reference Ø resting & post-exercise HR; Ø resting & post-exercise BP; Ø exercise T
rect; Ø exercise sweat rate; Ø post-exercise body mass; Ø post-exercise hemoglobin, hematocrit, & plasma volume; Ø post-exercise cortisol, aldosterone, renin, vasopressin, angiotensin I & II, & atrial peptide; Ø post-exercise urine volume, sodium, potassium, creatinine, and specific gravity; Ø reported muscle dysfunction; Ø RPE; Ø exercise performance 30 min cycling at 60 to 70% VO
2peakfollowed by three 10 s maximal sprints in an environmental chamber set at 37
C and 80% relative humidity
Volek
etal., 2001 Ø post-exercise body mass; Ø plasma volume; Ø exercise performance; Ø reported muscle dysfunction
Exercise and rest conducted in an environmental chamber set at 32
C and 50% relative humidity; 20 min rest in environmental chamber, five 5 s maximal cycling sprints, 75 min intermittent cycling (to reduce body mass 3 to 5%), 20 min rest in environmental chamber, five 5 s maximal cycling sprints, 75 min intermittent cycling, 20 min in environmental chamber, fiv e 5 s maximal cycling sprints
Vogel
etal., 2000 Ø resting hematocrit; Ø resting & exercise HR; ↓ exercise T
rect60 min cycling at 60% VO
2maxin an environmental chamber set at 37
C and 25% relative humidity Kern
etal., 2001 Ø time to exhaustion; ↓ exercise HR; ↓ RPE; ↓ exercise T
rect&T
body; ØT
skin; ↓ exercise sweat rate; Ø sweat loss; Ø exercise metabolic rate, VO
2, VCO
2,V
E, RER; Ø exercise plasma volume
Cycling to exhaustion at 63% VO
2maxin an environmental chamber set at 30
C and 70% relative humidity Kilduff
etal., 2004 Ø exercise T
rect,T
skin,T
body; Ø reported thermal sensation 40 min cycling at 55% VO
2maxin an environmental chamber set at 39
C and 26% relative humidity
Mendel
etal., 2005 Ø post-dehydration and post-exercise body mass; Ø exercise sweat loss; Ø exercise T
rect,T
skin; Ø exercise VO
2, HR, BP, MAP, lactate; Ø perceived environmental symptoms; Ø exercise plasma osmolality, volume, lactate, protein, sodium, potassium; ↑ post-dehydration plasma osmolality; ↑ exercise plasma glucose; ↓ post-exercise urine osmolality; ↑ resting, pre-exercise, and post-exercise urine specific gravity; Ø resting urine osmolality, specific gravity, color, volume
120 min cycling/treadmill walking in an environmental chamber set to 33.5
C and 41% relative humidity (to reduce body mass 2%), 80 min of alternatively running, walking, and standing
Watson
etal., 2006 Note: Ø indicates no effect of creatine; ↓ indicates a decrease following creatine ingestion; ↑ indicates an increase following creatine ingestion. HR = heart rate, BP = blood pressure, T
rect= rectal temperature, T
body= body temperature, T
skin= skin temperature, RPE = rating of perceived exertion, VO
2= oxygen consumption, VCO
2= carbon dioxide production, V
E= ventilation, RER = respiratory exchange ratio, MAP = mean arterial pressure.
concentration-dependent (i.e., a first-order process). This increase in stores can make the body appear to have a larger muscle mass than accounted for in the ideal body weight parameter of the Cockroft-Gault equation.
Clinical studies examining changes in serum creatinine with supplementation have found serum creatinine either does not change or increases but remains in the normal range ( ∼ 0.5 to 1.5 mg/dL for adults) (Table 3). Some concern has been raised by this increase because it is assumed a rise in serum creatinine indicates reduced kidney function. However, studies using both serum and urine creatinine to estimate renal function in healthy individuals (Kreider et al., 2003; Mihic et al., 2000; Poortmans and Francaux, 1999) and patients (Groeneveld et al., 2005;
Louis et al., 2003; Tarnopolsky et al., 2004; Tarnopolsky and Raha, 2005) have found no change in kidney function. Recently, it was reported that 16 months of creatine supplementation had no effect on plasma urea and micro-albuminuria (indirect markers of renal dysfunction) in 175 patients with amyotrophic lateral sclerosis (ALS) (Groeneveld et al., 2005). No changes in renal function have been noted in dystrophic patients as well (Louis et al., 2003).
Since Harris et al. (1992) first demonstrated that muscle creatine levels could be increased with oral creatine supplementation, there have been over 200 clinical studies (through 2006) examining the impact of creatine supplementation. Of the hundreds of clinical studies examining the effects of creatine supplementation, and the thousands of exposures to creatine through these studies and through use by the general population, we are aware of three case studies where individuals developed renal dysfunction during creatine ingestion (Koshy et al., 1999; Pritchard and Kalra, 1998; Revai et al., 2003).
In the first case study, a 20-year old male with nausea, vomiting and bilateral flank pain was consuming 20 g/d creatine (5 g four times a day) for four weeks prior to hospital admittance (Koshy et al., 1999). His serum creatinine was 1.4 mg/dL and urine analysis was positive for protein and red blood cells. Renal biopsy revealed acute focal interstitial nephritis and focal tubular injury. The patient did recover during his hospital admission. Most cases of interstitial nephritis are hypersensitivity reactions to medications such as non-steroidal anti-inflammatory drugs or antibiotics; in addition, obstruction of the tubules can cause this pathology as well. There was no evidence of inflammation hypersensitivity to creatine or renal obstruction as possible causes of the nephritis in this patient. It is possible that the dysfunction was caused by changes in osmotic gradient as seen with compounds such as mannitol.
The second case study involved a 25-year old male with focal segmental glomeru-
losclerosis with relapsing steroid responsive nephrotic syndrome (Pritchard and
Kalra, 1998); he was taking cyclosporine for the previous 5 years to minimize
nephrotic episodes and drug concentrations were within the therapeutic range. The
patient had a history of normal renal function but the patient’s creatinine clearance
started to decline over time. The patient admitted to taking 15 g/d creatine (5 g three
times a day) for 1 week followed by 2 g/d maintenance therapy. One month after
stopping the creatine supplement, creatinine clearance returned to normal. A later
282 Persky and Rawson
Table 3. Clinical studies examining serum creatinine (or creatinine clearance) responses during creatine supplementation. Serum creatinine is used as a clinical marker of renal function (normal limits: 0.5 to 1.5 mg/dL). The table summarizes data from 21 studies with creatine supplementation regimes ranging from 2 to 30 g/d for 1 d to 5.6 yrs. “load” = loading dose; “maint” = maintenance dose .
Study Finding Number of Studies
Dose Amount Duration Range
References
Studies finding no change in serum creatinine
12 15.75 g/d (load) 5 g/d (maint)
5 d
up to 21 months
Kreider et al., 2003
20 g/d 5 d Robinson et al., 2000 #
20 g/d 5 d Poortmans et al., 1997
3 to 30 g/d 10 mo to 5 yr Poortmans and Francaux, 1999 10 g/d Up to 310 d Groeneveld et al., 2005
2 g 1 d Harris et al., 1992
21 g/d 10 d Poortmans et al., 2005
2.5 g 1 d Harris et al., 2004
20 g/d (load) 5 g/d (maint)
5 d 3 yr
Schroder et al., 2005
20 g/d 2 d Mendes et al., 2004
3 g/d 3 mo Louis et al., 2003
20 g/d (load) 5 g/d (maint)
5 d 3-4 d
Parise et al., 2001
Studies finding an increase in serum creatinine but within normal limits
8 20 g/d (load)
3 g/d (maint) 5 d 8 wk
Robinson et al., 2000 #
20 g 1 d Schedel et al., 1999
20 g/d 5 d Kamber et al., 1999
20 g/d 5 d Mihic et al., 2000
5 g/d 16 wk Tarnopolsky et al., 2004
0.3 g/kg/d 7 d Volek et al., 2001
10 g/d 10 wk Tarnopolsky and Raha, 2005
13.7 ± 10.0 g/d (load) 9.7 ± 5.7 g/d (maint)
0.8 to 4 yr Schilling et al., 2001
Studies finding an increase in serum creatinine above normal limits
2 5 to 20 g/d 0.25 to 5.6 yr Mayhew et al., 2002
∗20 g/d 5 d Skare et al., 2001
∗
However, serum creatinine was not different from control group.
# There was no difference in serum creatinine after the initial 20 g/d loading phase, but serum creatinine did increase after the 8-week maintenance phase.
study found that cyclosporine does impact the kinetics of creatine transport, and the
interaction of cyclosporine with creatine might explain the renal dysfunction (Tran
et al., 2000).
In the third case study (full publication is available in Hungarian), the patient was “continuously” taking a “large quantity” of the anabolic-androgenic steroid methandion and 200 grams of creatine per day and subsequently developed diffuse membranoproliferative glomerulonephritis type I (Revai et al., 2003). In all three case studies, the patients either had previous renal disease (i.e., glomerulosclerosis with relapsing nephrotic syndrome) or ingested 4 to 100 times the recommended daily amount of creatine for extended periods of time with or without other anabolic agents. Conversely, several human clinical trials have been published demonstrating that creatine has no adverse effects on renal health (see Table 3) in individuals ingesting creatine supplements for up to five years.
2.4. Other
Although the effects of creatine supplementation on muscle function, thermoreg- ulation, and renal function comprise the bulk of the available safety data, several other areas have been studied. These include the effects of creatine on gastroin- testinal, hepatic, and cardiovascular health, production of undesirable metabolites subsequent to creatine supplementation, and product impurities.
2.4.1. Gastrointestinal, hepatic, and cardiovascular health
Anecdotal reports of gastrointestinal distress and diarrhea have been associated with creatine ingestion. Potentially, this could result from the ability of creatine to draw water into the intestine in a similar manner to how creatine draws water into the muscle. This could be prevented by ingestion of smaller quantities of creatine per serving, ingesting creatine in a liquid dosage form compared to a solid dosage form, and avoiding fruit juice consumption which may further increase the discomfort because of the osmotic potential of fructose.
To date, there are no reports of hepatic or cardiovascular dysfunction from clinical trials of creatine supplementation. Several studies have shown that creatine does not impact blood-based liver function tests (Kamber et al., 1999; Kreider, 2003;
Mayhew et al., 2002; Robinson et al., 2000). Further, systolic and diastolic blood pressure appear to be unaffected by creatine supplementation in young (Mihic et al., 2000) and older subjects (Rawson et al., unpublished observations). Earnest et al. (1996) reported decreased total cholesterol (6%), triglycerides (26%), and very low density lipoprotein in hypercholesterolemic men and women (32 to 70 yrs) supplemented with creatine for 56 days. However, Volek et al. (2000) found no additional effect of creatine on blood lipids when combined with resistance exercise training.
There is one case study related to creatine ingestion and cardiac dysfunction. A 30
year-old vegetarian male developed diarrhea and cramps after one month of creatine
supplementation, and subsequently changed to a different creatine supplement
and developed palpitations and dyspnea (Kammer, 2005). The patient underwent
chemical conversion and cardiac catheterization to correct the arrhythmia. It is
unknown what role creatine played in this case.
284 Persky and Rawson
2.4.2. Metabolites
There is some concern that creatine may form formaldehyde through a minor metabolic pathway, and in this regard, it was recently hypothesized that creatine supplementation could be cytotoxic (Yu and Deng, 2000). Creatine can be converted to formaldehyde and hydrogen peroxide, and formaldehyde has the potential to cross-link proteins and DNA leading to cytotoxicity. Yu and Deng (2000) did find an increase in urine formaldehyde after creatine administration; however, they did not measure markers of protein or DNA cross-linking or measures of oxidative stress. Another study examined urinary methylamine, formaldehyde and formate with creatine supplementation (Poortmans et al., 2005). These investigators found increases in both methylamine and formaldehyde when subjects ingested 21 g/d for 14 d. The increase in methylamine was still below the upper-limit of normal but for formaldehyde, no safety range has been established.
2.4.3. Impurities
In the United States, creatine is not regulated for its processing and impurities, so as with other dietary supplements, there is some concern that contaminants may lead to adverse effects with creatine use. Benzi (2000) theorized that because creatine is produced from the reaction of sarcosine and cyanamide, several possible contaminants such as creatinine, dicyandiamide, dihydrotriazines, and ions such as arsenic could be produced. Although many creatine manufacturers provide a certificate of analysis with their products that addresses the issue of impurities, these findings have not been confirmed in many independent analyses. At least two studies examined creatine product quality with respect to percent labeled claim (Dash and Sawhney, 2002; Persky et al., 2003). Both studies found powdered creatine products contained >99% creatine and did not note any unidentified peaks upon liquid chromatography.
3. FUTURE DIRECTIONS
The majority of information regarding the safety of creatine supplementation is
available from relatively small clinical studies that lasted short periods of time, and
examined healthy volunteers. Studies involving patients, larger numbers of subjects,
long periods of time, and over a dose range are lacking. Investigators should assess
and report on adverse events even by simple questionnaire. If possible, conclusions
should be drawn whether adverse events were likely or unlikely related to the
treatment. In addition, blood or muscle creatine levels should be evaluated to help
relate adverse events to a systemic concentration of creatine, which could help assess
whether side effects are dose-related. Finally, placebo controls allow judgments to
be made whether the use of creatine is more likely to cause an adverse event than in
the un-supplemented condition. For example, Table 4 summarizes adverse events
from a study in patients with amyotrophic lateral sclerosis treated with creatine
(Groeneveld et al., 2005). The use of a placebo group allows conclusions to be
drawn based on a potentially increased risk of a certain side effect. Muscle cramps
Table4
. Percentage of ALS patients who had an adverse event. Time average ratio indicates the relative prevalence of adverse events during the study. 1.0 = prevalence in the creatine (Cr) and placebo groups (Pl); < 1.0: less events in the creatine group; > 1.0: more events in the creatine group. Data adapted Groeneveld
etal.(2005) . System Event Treatment 1 month 2 months 4 months 8 months 12 months At any time Time Average Ratio Muscle Cramps Pl 61 70 79 69 73 91 Cr 62 73 78 73 67 95 1.0 Cramps on Exertion Pl 37 33 28 38 45 62 Cr 24 36 38 42 38 70 1.1 Limb Edema Pl 18 9 18 29 45 46 Cr 21 26 35 42 42 54 1.4 Gastrointestinal Nausea Pl 13 7 7 7 14 24 C r 6 69982 3 0.99 Vomiting Pl 2 40491 0 C r 3 33081 0 0.76 Diarrhea Pl 11 88992 4 Cr 14 3 9 13 17 35 1.3 Constipation Pl 11 9 16 22 23 35 Cr 15 4 9 22 42 38 1.1 General Discomfort P l 1 1 78451 8 Cr 3 6 6 9 13 19 1.4 Reflux Pl 7 12 15 16 9 27 Cr 12 9 7 13 17 28 0.85 Skin Rash Pl 6 7 7 20 23 24 Cr 5 8 7 13 13 19 0.71 Pruritus Pl 7 8 25 27 23 35 Cr 13 13 15 18 33 24 0.85
286 Persky and Rawson
appear to be equally likely in this patient population whether on creatine or placebo whereas general gastrointestinal discomfort appears more prevalent in the creatine group.
4. CONCLUSION
The available data suggest that there are few adverse effects associated with creatine supplementation when ingested at recommended doses. Anecdotally, muscle dysfunction appears to be commonly associated with creatine supplemen- tation, but data do not support this. Additionally, anecdotal reports of an association between creatine supplementation and impaired thermoregulation or dehydration are not supported by data. Although case reports suggest possible renal related side effects, most clinical studies show no indication of renal dysfunction with creatine use. As creatine supplementation becomes increasingly used as a potential intervention in clinical populations, larger scale studies should provide useful infor- mation into potential side effects, their severity and their incidence rate.
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